Perinatal, Paediatric and Adolescence: What are the HIV priorities?

Graham P TaylorProfessor of Human Retrovirology/Honorary Consultant

PERINATALAbigail 18 years.Known HIV positive 6 years.Attending sixth-form college.On a fixed dose combination, one tablet, once per dayBooks at 22 weeksCD4 count 220 cells/LHIV viral load 132,453 HIV RNA copies/ml

Non-adherentWhat is your diagnosis?

PERINATALYou offer Abigail:CNS/ Psychology adherence supportNew therapy: Tenofovir/FTC/Darunavir/ritonavirReviewed 26/40HIV viral load 96,432 HIV RNA copies/ml

Non-adherentWhat is your diagnosis?

PERINATALAbigailEight weeks later: presents in labourTreatment: sd Nevirapine,

double dose Tenofovir, sd Raltegravir

Delivers vaginally

Baby treatment zidovudine/lamivudine/nevirapine

What do you want to know?

Is the baby already infected?

5

Final Results From the 6-Year Randomized CHER

(Children with HIV Early antiRetroviral) Trial in South Africa Mark Cotton, Avy Violari, Diana Gibb, Kennedy Otwombe, Deirdre

Josipovic, Ravindre Panchia, Patrick Jean-Phillipe, Edward Handelsman, James McIntyre and Abdel Babiker

CROI 2012

6

CHER Trial Part A n=375

HIV infection diagnosed before 12 weeks and CD4% ≥25%

ART-Deferred Defer ART until

clinical progression or CD4% dropN=125

ART-40W Early ART to 40

weeks; then STOP, until progression

N=125

ART-96W Early ART to 96

weeks; then STOP, until progression

N=125

Follow: up to 6 yearsPrimary endpoint: time to failure of first line ART

ART (start or re-start) when CD4% <20% or clinical event

1st-line ART: Kaletra® + ZDV+3TC

Design

Proportion of children on ART

7

Overall proportion of time spent on ART

ART-Def 81%ART-40W 70%ART-96W 69%

Week on study

ART-Def

ART-40W

ART-96W

Pro

porti

on o

n A

RT

0.00

0.25

0.50

0.75

1.00

Pro

porti

on re

achi

ng p

rimar

y en

dpoi

nt

126 116 111 107 106 83ART-96W125 114 106 99 97 74ART-40W125 97 94 91 89 72ART-Def

Number at risk

0 48 96 144 192 240Weeks since randomisation

ART-Def ART-40W ART-96W

HR (95% CI) relative to ART-DeferredART-40W: 0.73 (0.46 – 1.17, p=0.19)ART-96W: 0.58 (0.35 – 0.96, p=0.03)

ART-40/96W: 0.65 (0.43 - 0.98, p=0.04)

Time to Primary Outcome ART-Deferred vs ART-40W vs ART-96W

Death or failure of 1st line ART

Progression to severe CDC B or CDC C or death

9

0.00

0.25

0.50

0.75

1.00

Pro

porti

on w

ith c

linic

al fa

ilure

126 105 96 89 88 68ART-96W126 106 85 83 82 67ART-40W125 79 72 71 70 57ART-Def

Number at risk

0 48 96 144 192 240Weeks since randomisation

ART-Def ART-40W ART-96W

HR (95% CI) relative to ART-DeferredART-40W: 0.5 (0.3 – 0.8, p=0.005)ART-96W: 0.4 (0.3 – 0.7, p=0.0003)

Pro

porti

on

Priority 1. Early diagnosis of infant infection

HIV infected children should be started on ART straight away as this prevents AIDS, death, severe neurological sequelae and preserves immune function.

Paediatric European Network for Treatment of AIDS Treatment Guideline 2016 update: antiretroviral therapy recommended for all children living with HIV

What test do you want in the baby?

1. HIV Ab2. HIV DNA3. HIV RNA

1. HIV Ab - is a test of maternal status2. HIV DNA – not affected by maternal or neonatal therapy3. HIV RNA - Sensitive and increasingly available

– maternal infection detected by this methodFalse negative if early HIV infection has been treated

transplacentally

More results - outcome 1At delivery maternal HIV viral load 4,377 HIV RNA copies/ml

Further history indicates that Abigail took Atripla intermittently

Baby: Day 1 sample HIV DNA detected

What are your treatment options?

Limited! - What’s available?

What are your treatment options?

a) pre-term and nil by mouth – ZDV IVb) Pre-term and enterally fed –

zidovudine/lamivudine/nevirapine/lopinavirc) Term and enterally fed -

zidovudine/lamivudine/nevirapine/lopinavir

Priority 2. Paediatric formulations and parenteral formulations

(1)safe and effective ART for children, (2)palatable and easy-to-swallow medications, (3)fixed-dose combinations to decrease pill burden, (4)once-a-day formulations to lengthen dosing intervals, (5)medications that are easy to transport and store, (6)formulations that are simple for caregivers to

administer

AIDS Res Treat. 2016; 2016: 1654938. Published online 2016 Jun 16. doi:  10.1155/2016/1654938The Need for Pediatric Formulations to Treat Children with HIVAdrienne F. Schlatter,  Andrew R. Deathe, and Rachel C. Vreeman 

Alternative scenario – Abigail’s baby is not infectedAt delivery maternal HIV viral load 4,377 HIV RNA

copies/ml

Further history indicates that she took Atripla intermittently

Baby: Day 1 sample HIV DNA not detected

Abigail has been taking her medications correctly for the last two weeks

and decides to breast feed her baby

WHO HIV and Infant Feeding Guidelines 2016

Mothers living with HIV should breastfeed for at least 12 months and may continue breastfeeding for up to 24 months or longer (similar to the general population) while being fully supported for ART adherence.

Breast-feeding related HIV Transmission during ARVs

Study Intervention (PP) Transmission Rate Reference

Vit A RCT n 103 156 288

Observational study15 months FU

Exclusive BF 25%Never BF 20%Mixed feeding 35%

Coutsoudis et al AIDS 2001;15:379-

387

DREAM n 341Mozambique

Observational studyHAART + 6/12 Excl BF

Observed 2.8%Expected 40%

Marazzi et al, PIDJ, 2009; 28:483-7

n 441Tanzania

Observational studyHAART + 6/12 Excl BF

6/52 4.1%6/12 5.1%

Kilewo et al, JAIDS, 2009; 52: 406-16

n 102Uganda

Observational studyHAART + 6/12 Excl BF

No Transmissions19% MR

Homsy et al, JAIDS, 2010;53:28-35

Maternal n 227Choice n 305

Breast FedFormula-Fed

0.5%0 %

Peltier et al, AIDS 2009;23:2415-2413

Mma Bana n 265Rwanda 265RCT 170

TrizivirCBV/KaletraCBV/NVP

0.7%0 %0 %

Shapiro et al, NEJM, 2010;362:2282-2294

BAN n 851Malawi 848RCT 668

CBV/NVP or KaletraInfant NVPNutritional supplements

3.0% 1.8%6.4%

Chesale et al, NEJM, 2010;362:2271-2281

Efficacy of WHO recommendation for continued breastfeeding and maternal cART

Ngoma M et al JIAS 2015;18 19352

Excl B

F

Com

plementary

BF

CO

BZDV/3TC/LPV/Rit from 14 – 26 GA weeks to beyond Cessation of Breast feeding

Priority 3. Long-term outcome data on transmission through breast-feeding whilst on cART – what is best?

Adolescent HIV

N 389 514 671 891 1150 1357 1509 1607 1645 433 577 779 1027 1251 1444 1569 1646 1541

Note: Data are for all children and young people alive who were ever in follow-up from 1996 onwards, including children who have since transferred to adult care; those who subsequently died or were lost to follow-up are excluded from the year of death or loss to follow-up. All paediatric infections are included, regardless of mode of acquisition (94% perinatal). CHIPS includes all diagnosed HIV-infected children known to be living in the UK/Ireland, of whom ~55% were born abroad. Data for 2013 are incomplete as subject to reporting delay.

Age of UK/Irish paediatric cohortby year of follow-up, 1996-2013

>60% 16+

HIV is the leading cause of death among adolescents in Africa• Adolescence is the only age group in which AIDS

deaths increased between 2005 and 2012 • 36.7 million people living with HIV - 1.8 million

between 10-19 years old – majority perinatally infected

• 2.1 million new HIV infections: 250,000 in 10-19 year olds in 2015

• Young women aged 15–24 years are disproportionately affected, accounting for 20% of all new diagnoses, even though they represent just 11% of the adult population

11 deaths Transfer: median age 17 yrs, CD4 120. At death: 21 yrs, CD4 27 Causes: suicide (2), end stage AIDS (3), respiratory infections (2) PML, CNS lymphoma, ICH and Toxoplasmosis. 9/11 mental health diagnosis All had treatable virus in year of death

What happens in chronic disease?

Renal transplant: 35% lost graft within 36 months of transfer Watson A 2000

Diabetes: 10-69% no medical f/up after paediatric care Pacaud D 1996, Frank M 1996

19.8% were LTFU in the year after turning 22 years. Independent associations with LTFU were:

1) Receiving care at an adult versus pediatric HIV clinic (AOR, 2.91; 95% CI, 1.42-5.93), 2) having fewer than four primary HIV visits/year (AOR, 2.72; 95% CI, 1.67-4.42), 3) Having antiretroviral therapy prescription (AOR, 0.50; 95% CI, .41-.60) LTFU was prevalent at each age transition, 

Agwu et al.

• 237 PaHIV median age 20 yrs• median age HIV diagnosis 6 yrs• 22% psychiatric diagnosis:

depression > psychosis > anxiety

• 25% psychological diagnosis: anxiety, depression, self harm, risk behaviours

• association with lower CD4 count (p<0.002)

Marthe Le Provost – AALPHI cohort

UK risk factors for Adolescent Mental Health

Black ethnicityMigrant population

Parental unemploymentLooked after child

Poverty

current smoking 1.32 (1.13, 1.54)illegal drugs 1.49 (1.15, 1.92)early sexual debut 1.33 (1.03, 1.72)eating disorder 1.44 (1.26, 1.74)antisocial acts 1.48 (1.26, 1.74)attempted suicide 2.24 (1.55, 3.24)

more likely to report 3 or > 4 simultaneous behaviours

JC Suris et al, 2007 J Begent CHIVA 2010

RISK BEHAVIOURS IN YOUTH WITH CHRONIC CONDITIONS

HIV TRANSITION @ Imperial

• 1988 Born in Romania

• 1996 Dual therapy

• 1999 Triple therapy

• Never full virological suppression

• 2001 CD4 110 - gastrostomy tube

• 2005 CD4 470, VL <50 for 4 yrs - tube out

KATIE – Childhood years

• 2006 DNA’d. PID, miscarriage, supportive partner

• 2006 HIV – ve son: premature

• 2007 CD4 20 - PEG

• 2008 Adherence poor despite MDT, partner, peers

• 2009 CD4 0 - Directly Observed Therapy

• 2010 VL <50, CD4 220 - lipodystrophy

• 2012 CD4 20 PCP

KATIE - Adolescence

Afternoons, walk-in, MDT, sexual health,

Contraception, peer support, vaccination, social care, finances

Confidential competent and caring

OPD REMINDERART ALARM

ART SWITCH PICADHERENCE APP

MD2Me – Generic 2/12 Web-based & text-delivered disease management and skill-based intervention with trends towards improved transition readiness

HUANG et al PEDIATRICS Volume 133;6, June 2014

ATTENDANCE

Text remindersWalk in any Wednesday – no questions askedIf DNA; calls, texts, letters, whats app, local service, past

paediatric healthcare team, community nursing, GPNever “discharged” due to DNARe-engage at crisis points – admission, transfer in if local

hospital

5/157 (3%) not seen in 900 in last year: HMP (2), agrophobia and alcoholism (1) – home visits and bloods, contactable by phone only (1), LTFU (1); university- GP trying to chase LTNP

• New partner• CD4 20• DRV/r mono5/2016 • VL <20 • CD4 582• Aged 28

Katie2013 -16

Priority 5: Long-acting ART –ECLAIR and LATTE-2

92% had SE mostly pain

Murray M et al CROI 2016

Cabotegravir Integrase Inhibitor oral T/2 40 hours,

IM nanosuspension T/2 20-40 days

Rilpivirine (RPV) T/2 oral 50h 300mg/ml nanosuspension IM T/2 30-90d. CAB + RPV oral was at least as effective as Efavirenz based triple therapy (LATTE)

Margolis D et al CROI 2014

Margolis D et al CROI 2016

Bridging Worlds: Perinatally infected youth in adult care

DR CAROLINE FOSTERIMPERIAL COLLEGE HEALTHCARE NHS TRUST LONDONSeptember 2016

Massive thanks to Caroline Foster our adolescent doctor!

RIVER - Research into eradication of HIV reservoirs

Early HIV infection

Quadruple Therapy

HIV Vaccination

Vorinostat ‘Kick’

Unmask latent infection

Anatomical hidden reservoirs – gut, genitalia, brainpoor HAART penetration

Functional reservoirs - long-lived latently infected cellsHIV infected central memory cells (TCM)HIV infected transitional memory cells (TTM)HIV infected T memory stem cells (Tscm) high proliferative potentialBuzon M et al CROI 2013

60 years of therapy from an early model NEW

Unmask latent infection

Histone deactelylase inhibitorsSodium valproateVorinostat

B-catenin inhibitorsStops stem cells from differentiating into

memory cells

T-cell activationIL-2Interferon-2bIL-7 – not effective in ERAMUNE

Histone acetylation and deacetylation

What was reported?

Suppression of HIV viral load with quadruple therapy

What was described?

HIV Cure

‘Functional cure’

10

100

1,000

10,000

100,000

0 5 10 15 20 25 30

Viral load

ART/carediscontinued

Months

Persaud et al. CROI 2013. Abst. 48LB

Virological studies to detect residual HIV in this very-early treated child

Proviral DNA Copies/10*6 cells

Cells tested /well(No replicates pos)

PBMC 24/1226/12

<2.74.2

122,000 (0/2)133,000 (1/6)

Resting CD4 T-cells 24/1226/12

<3.5<2.5

96,500 (0/3)134,000 (0/6)

Enriched foractivated T-cells

24/1226/12

< 2.2<2.6

154,000 (0/6)130,000 (0/6)

Monocyte-derivedadherent cells

24/1226/12

37.6<11.5

14,300 (1/3) 29,000 (0/6)

HIV RNA

Plasma 24/1226/12

1 copy/ml<2 copies/ml

n/an/a

Infectious virus fromresting CD4+ 24/12 Not

recovered n/a

Persaud et al. CROI 2013. Abst. 48LB